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Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway.
Am J Respir Cell Mol Biol. 2014 Mar; 50(3):526-37.AJ

Abstract

Transepithelial sodium transport via alveolar epithelial Na(+) channels (ENaC) and Na(+),K(+)-ATPase constitutes the driving force for removal of alveolar edema fluid. Alveolar hypoxia associated with pulmonary edema may impair ENaC activity and alveolar Na(+) absorption through a decrease of ENaC subunit expression at the apical membrane of alveolar epithelial cells (AECs). Here, we investigated the mechanism(s) involved in this process in vivo in the β-Liddle mouse strain mice carrying a truncation of β-ENaC C-terminus abolishing the interaction between β-ENaC and the ubiquitin protein-ligase Nedd4-2 that targets the channel for endocytosis and degradation and in vitro in rat AECs. Hypoxia (8% O2 for 24 h) reduced amiloride-sensitive alveolar fluid clearance by 69% in wild-type mice but had no effect in homozygous mutated β-Liddle littermates. In vitro, acute exposure of AECs to hypoxia (0.5-3% O2 for 1-6 h) rapidly decreased transepithelial Na(+) transport as assessed by equivalent short-circuit current Ieq and the amiloride-sensitive component of Na(+) current across the apical membrane, reflecting ENaC activity. Hypoxia induced a decrease of ENaC subunit expression in the apical membrane of AECs with no change in intracellular expression and induced a 2-fold increase in α-ENaC polyubiquitination. Hypoxic inhibition of amiloride-sensitive Ieq was fully prevented by preincubation with the proteasome inhibitors MG132 and lactacystin or with the antioxidant N-acetyl-cysteine. Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport.

Authors+Show Affiliations

1 Université Paris 13, Sorbonne Paris Cité, Laboratoire Réponses Cellulaires et Fonctionnelles à l'Hypoxie (EA 2363), Bobigny, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24093724

Citation

Gille, Thomas, et al. "Hypoxia-induced Inhibition of Epithelial Na(+) Channels in the Lung. Role of Nedd4-2 and the Ubiquitin-proteasome Pathway." American Journal of Respiratory Cell and Molecular Biology, vol. 50, no. 3, 2014, pp. 526-37.
Gille T, Randrianarison-Pellan N, Goolaerts A, et al. Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway. Am J Respir Cell Mol Biol. 2014;50(3):526-37.
Gille, T., Randrianarison-Pellan, N., Goolaerts, A., Dard, N., Uzunhan, Y., Ferrary, E., Hummler, E., Clerici, C., & Planès, C. (2014). Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway. American Journal of Respiratory Cell and Molecular Biology, 50(3), 526-37. https://doi.org/10.1165/rcmb.2012-0518OC
Gille T, et al. Hypoxia-induced Inhibition of Epithelial Na(+) Channels in the Lung. Role of Nedd4-2 and the Ubiquitin-proteasome Pathway. Am J Respir Cell Mol Biol. 2014;50(3):526-37. PubMed PMID: 24093724.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway. AU - Gille,Thomas, AU - Randrianarison-Pellan,Nadia, AU - Goolaerts,Arnaud, AU - Dard,Nicolas, AU - Uzunhan,Yurdagül, AU - Ferrary,Evelyne, AU - Hummler,Edith, AU - Clerici,Christine, AU - Planès,Carole, PY - 2013/10/8/entrez PY - 2013/10/8/pubmed PY - 2014/4/25/medline SP - 526 EP - 37 JF - American journal of respiratory cell and molecular biology JO - Am J Respir Cell Mol Biol VL - 50 IS - 3 N2 - Transepithelial sodium transport via alveolar epithelial Na(+) channels (ENaC) and Na(+),K(+)-ATPase constitutes the driving force for removal of alveolar edema fluid. Alveolar hypoxia associated with pulmonary edema may impair ENaC activity and alveolar Na(+) absorption through a decrease of ENaC subunit expression at the apical membrane of alveolar epithelial cells (AECs). Here, we investigated the mechanism(s) involved in this process in vivo in the β-Liddle mouse strain mice carrying a truncation of β-ENaC C-terminus abolishing the interaction between β-ENaC and the ubiquitin protein-ligase Nedd4-2 that targets the channel for endocytosis and degradation and in vitro in rat AECs. Hypoxia (8% O2 for 24 h) reduced amiloride-sensitive alveolar fluid clearance by 69% in wild-type mice but had no effect in homozygous mutated β-Liddle littermates. In vitro, acute exposure of AECs to hypoxia (0.5-3% O2 for 1-6 h) rapidly decreased transepithelial Na(+) transport as assessed by equivalent short-circuit current Ieq and the amiloride-sensitive component of Na(+) current across the apical membrane, reflecting ENaC activity. Hypoxia induced a decrease of ENaC subunit expression in the apical membrane of AECs with no change in intracellular expression and induced a 2-fold increase in α-ENaC polyubiquitination. Hypoxic inhibition of amiloride-sensitive Ieq was fully prevented by preincubation with the proteasome inhibitors MG132 and lactacystin or with the antioxidant N-acetyl-cysteine. Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport. SN - 1535-4989 UR - https://www.unboundmedicine.com/medline/citation/24093724/Hypoxia_induced_inhibition_of_epithelial_Na_+__channels_in_the_lung__Role_of_Nedd4_2_and_the_ubiquitin_proteasome_pathway_ L2 - https://www.atsjournals.org/doi/10.1165/rcmb.2012-0518OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -